Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[O:12])=[N:9][CH:10]=1)[CH3:3].[CH3:13][Mg]Br.Cl>O1CCCC1>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([OH:12])[CH3:13])=[N:9][CH:10]=1)[CH3:1]
Reactant: CC(C)Oc1ccc(C=O)nc1
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C(C)O)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.7 %

Procedure:
5-(1-Methylethoxy)picolinaldehyde (24 mg, 0.145 mmol) was dissolved in tetrahydrofuran (1.5 mL), added methylmagnesium bromide (230 μL, 0.218 mmol) under ice-cold conditions, and the mixture was stirred at 0° C. for 0.5 hours. The mixture was further stirred at room temperature for 0.5 hours. The reaction solution was added 1N aqueous solution of hydrochloric acid and an aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and 1-[5-(1-methylethoxy)pyridin-2-yl]ethanol (27 mg (yield 98%)) was obtained as a brown oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][Cl:7].[CH2:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14]>C(#N)C.C(OCC)C>[Cl-:7].[CH2:13]([N+:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=1)[CH3:14]
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: CCN(CC)CC
Solvent: CCOCC
Solvent: CC#N
Product: CC[N+](CC)(CC)Cc1cccc(C(F)(F)F)c1
Product: [Cl-]
Temperature: 85 °C

Procedure:
A mixture of 15.3 grams (0.08 mole) of 3-(trifluoromethyl)benzyl chloride and 8.0 grams (0.086 mole) of triethylamine in 50 milliliters of acetonitrile was heated 6 hours at 85° C. The mixture was then stirred over a weekend at room temperature. The crystals which formed were slurried in ethyl ether. The crude product was recovered by filtration and extracted with 600 milliliters of hot methyl ethyl ketone and 0.50 ml of methylene dichloride. The triethyl-(3-trifluoromethyl)benzyl) ammonium chloride was recoved by filtration in a yield of 13.7 grams. The product melted at 213°-215° C. The structure of the compound was confirmed by NMR.
Reaction SMILES: [NH2:1][C@:2]12[C@@H:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C@H:6]1[CH2:5][O:4][C:3]2=[O:14].[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][CH:23]=2)[CH:18]=1>N1C=CC=CC=1>[O:14]=[C:3]1[O:4][CH2:5][C@H:6]2[C@:2]1([NH:1][S:27]([C:25]1[S:26][C:22]([C:19]3[CH:18]=[C:17]([C:16]([F:15])([F:31])[F:32])[O:21][N:20]=3)=[CH:23][CH:24]=1)(=[O:28])=[O:29])[C@H:7]2[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2cc(C(F)(F)F)on2)s1
Reactant: N[C@@]12C(=O)OC[C@@H]1[C@@H]2c1ccccc1
Solvent: c1ccncc1
Product: O=C1OC[C@@H]2[C@H](c3ccccc3)[C@]12NS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)on2)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
(1R*,5R*,6R*)-1-amino-6-phenyl-3-oxa-bicyclo[3.1.0]hexan-2-one (0.14 g, 0.74 mmol) was dissolved in 3 mL of pyridine. After cooling to 0° C., 5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonyl chloride (0.31 g, 0.96 mmol) was added in one portion. The reaction mixture was warmed to room temperature and stirred overnight. After concentration, the reaction mixture was diluted with EtOAc, washed with 10% citric acid, water (×2), 5% NaHCO3 and brine and dried over Na2SO4. After concentration, the crude product was purified by column chromatography using 2:1 hexanes/EtOAc to afford 0.26 g (75%) of the desired product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([OH:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:32][C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)([CH3:4])([CH3:3])[CH3:2].[CH2:40]([O:47][C:48]([CH2:50][S:51][CH2:52][C:53](O)=[O:54])=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([O:21][C:53](=[O:54])[CH2:52][S:51][CH2:50][C:48]([O:47][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:49])[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[O:32][C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CSCC(=O)OCc1ccccc1
Reactant: CC(C)(C)c1ccc(CCC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Product: CC(C)(C)c1ccc(CCC(CC2CCCCC2)OC(=O)CSCC(=O)OCc2ccccc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21

Procedure:
Following a procedure similar to that described in Preparation 25, but using N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 12) and 2-(benzyloxycarbonylmethylthio)acetic acid as starting materials, in relative proportions similar to those used in that Preparation, the title compound was obtained as a foam-like material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[CH:14]=[CH:15][S:16][C:11]3=[C:10]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]([NH2:25])=O)[CH2:19][CH2:18]3)[CH:9]=2)=[CH:4][CH:3]=1.[CH:26]([NH:28][NH2:29])=O.C(O)=O>O(Cl)Cl.[P].C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[CH:14]=[CH:15][S:16][C:11]3=[C:10]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[N:25]=[CH:26][NH:28][N:29]=4)[CH2:19][CH2:18]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NNC=O
Reactant: NC(=O)C1CCN(c2cc(-c3ccc(F)cc3)nc3ccsc23)CC1
Agent: ClOCl
Agent: [P]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2cc(N3CCC(c4nc[nH]n4)CC3)c3sccc3n2)cc1
Yield: 5.8 %

Procedure:
A suspension of 1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)piperidine-4-carboxamide (100 mg, 0.32 mmole) in phosphorus oxochloride (5 mL) is refluxed for about 30 minutes. After the excess phosphorus oxychloride is removed under vacuum, the residue is treated with ethyl acetate (5 mL), and ice-water (10 mL). The mixture is extracted with ethyl acetate (3×10 mL). The combined organic layers are washed with brine, dried over sodium fate, filtered, and concentrated. The residue is dissolved in toluene (5 mL) and then formic hydrazide (100 mg, 1.7 mmole) and formic acid (0.05 mL) are added. The reaction mixture is refluxed for about 16 hours. It is then cooled, diluted with ethyl acetate (15 mL), and washed with water (3×15 mL). The organic layer is dried over sodium sulfate, filtered, and concentrated. The residue is purified by preparative tlc to give 5-(4-fluorophenyl)-7-[4-(1H-1,2,4-triazol-3-yl)-1-piperidinyl]thieno[3,2-b]pyridine (7 mg, 6% yield) as a white solid. This material is dissolved in ethyl acetate (1 mL), saturated with HCl (2 mL), and then concentrated to afford 5-(4-Fluorophenyl)-7-[4-(4H-1,2,4-triazol-3-yl)piperidyl]thioheno[3,2-b]pyridine hydrochloride (compound 2) as greasy oil. Trituration with ether, filtration and drying in vacuo affords the desired product as a solid. m.p. >300° C. (dec).
Reaction SMILES: O=P(Cl)(Cl)Cl.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.[OH-].[Na+].CN([CH:21]=[O:22])C>>[CH:21]([C:10]1[S:6][C:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)=[O:22]
Reactant: c1csc(-c2cccs2)c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2cccs2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
250 ml of DMF in 1 liter flask was added 50.2 ml of POCl3 and stirred for 1 hour at 0° C. to form a complex. 83 g of 2,2'-bithiophene was dissolved in 200 ml of DMF and then added into the complex. After the solution was stirred at 10° C. for 0.5 hour, then the temperature was raised to 40° C. and stirred for 20 hours. The orange viscous product was poured into 3 l beaker and crushed ice cubes were added and stirred for 0.5 hour and then neutralized with 600 ml of 10% aqueous NaOH solution. After the solution was extracted with chloroform, washed with water and dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure and the crude product was purified by column chromatography. 90 g of product was thus obtained and the melting point thereof was 56°-57° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[O:10][N:9]=[CH:8][C:7]=1[C:11]([OH:13])=O>CN(C)C=O>[CH3:5][C:6]1[O:10][N:9]=[CH:8][C:7]=1[C:11]([Cl:3])=[O:13]
Reactant: Cc1oncc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1oncc1C(=O)Cl

Procedure:
Thionyl chloride (118 g) was added to 5-methylisoxazol-4-yl carboxylic acid (42 g) and stirred at room temperature as dimethylformamide (0.2 ml) was added. The solution was heated under reflux for 2 hours with stirring. Excess thionyl chloride was removed in vacuo at 50° C., then the residue was distilled through a 15 cm Vigreaux column at reduced pressure to give an oil, b.p. 32°-34° C./0.1 mm Hg.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:4].[Br:20]Br>C(O)(=O)C.[O-]S([O-])(=S)=O.[Na+].[Na+]>[Br:20][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:19])([CH3:18])[CH3:1])=[C:7]([C:12]2[N:13]=[CH:14][CH:15]=[CH:16][N:17]=2)[CH:8]=1
Reactant: CC(C)(C)C(=O)Nc1ccccc1-c1ncccn1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)Nc1ccc(Br)cc1-c1ncccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 113 %

Procedure:
To a room temperature suspension of 2,2-dimethyl-N-(2-pyrimidin-2-yl-phenyl)-propionamide (˜117 grams, 437 mmoles) in acetic acid (1 L) was added bromine (67 mL, 1.31 moles) as a solution in 100 mL of acetic acid over a 1 hour period. The heterogenous mixture was stirred at room temperature for 5 hours over which time a thick precipitate formed. The mixture was then poured over ice, diluted with 1N Na2S2O3 (2 L), and stirred for 1 hour. The solids were filtered, resuspended in water (2 L), stirred for 1 hour, then filtered and washed with water again. The resulting solids were pumped to dryness at 50° C., resuspended in HOAc (1 L), and treated with bromine (22 mL, 430 mmoles) in acetic acid solution (20 mL) over a 20 minute period. The resulting heterogenous mixture was stirred for 5 hours, then quenched and treated as described above. The resulting solids were vacuum dried at 50° C. to afford the title compound (165 grams) as a tan powder.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N+:15]([O-:17])=[O:16])=[CH:6][C:7]([N+:12]([O-:14])=O)=[C:8]([CH:11]=2)[CH:9]=O)[CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.[C-:26]#[N:27].[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C.CO>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]2[C:9]([C:26]#[N:27])=[C:8]3[C:7]([CH:6]=[C:5]([N+:15]([O-:17])=[O:16])[C:4]([CH:1]4[CH2:2][CH2:3]4)=[CH:11]3)=[N+:12]2[O-:14])=[CH:21][CH:20]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=Cc1cc(C2CC2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: N#Cc1c2cc(C3CC3)c([N+](=O)[O-])cc2[n+]([O-])n1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 108.4 %

Procedure:
To a stirred suspension of (iv) (20 g, 0.09 mol) in acetic acid (400 mL) was added 4-chloroaniline (21.6 g, 0.17 mol) and the reaction heated at 60° C. to obtain a complete solution. To this solution was added sodium cyanide (20 g, 0.41 mol) portionwise over 20 min. The reaction mixture was stirred for 5 min whereupon acetic anhydride (6 mL) was added. Upon the formation of a precipitate, an additional quantity of sodium cyanide (20 g, 0.41 mol) was added portionwise. After stirring for 1 h, the reaction mixture was cooled to RT, diluted with MeOH (30 ml) and the solids separated by filtration. The solid cake was dissolved in chloroform (400 ml) and the organics washed with water (2×100 ml), dried (MgSO4) and concentrated in vacuo to give the intermediate 2-(4-chlorophenyl)-5-cyclopropyl-6-nitro-2H-indazole-3-carbonitrile 1-oxide (34.6 g). ESI-MS m/z calculated for [M+H]+: 355.1. found: 355.2. 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.72-7.50 (m, 5H), 2.44-2.30 (m, 1H), 1.18-1.05 (m, 2H), 0.85-0.71 (m, 2H).
Reaction SMILES: C([NH:3][C@H:4]([C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH2:5][C:6](=[O:8])[OH:7])=O.Cl.[CH3:24]O>>[CH3:24][O:22][C:20](=[O:21])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:9](=[O:10])[C@H:4]([CH2:5][C:6](=[O:8])[OH:7])[NH2:3]
Reactant: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O

Procedure:
A process comprising reacting N-formyl-aspartic anhydride with l-phenylalanine in glacial acetic acid to form N-formyl-α-L-aspartyl-L-phenylalanine, removing the formyl group from N-formyl-α-L-aspartyl-L-phenylalanine by hydrolysis with an aqueous solution of hydrogen chloride and esterifying the resulting α-L-aspartyl-L-phenylalanine with methanol in the presence of hydrogen chloride to form α-L-aspartyl-L-phenylalanine methyl ester and recovering the α-L-asparatyl-L-phenylalanine methyl ester.
Reaction SMILES: [C:1]1(C)[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH2:11](Cl)[CH2:12][CH2:13][CH3:14].S(=O)(=O)(O)O.[CH2:21](O)CCC>O>[CH3:11][CH:12]([CH2:13][CH3:14])[CH2:21][O:7][C:6]1[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: CCCCO
Reactant: CCCCCl
Reactant: Cc1ccccc1O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCC(C)COc1ccccc1
Reaction time: 2 h

Procedure:
540 g (5.0 mol) o-cresol, 500 g n-butanol and 560 g (5.0 mol) 50% (m/m) potassium hydroxide solution are initially introduced and heated under reflux, the water being removed azeotropically. 463 g (5.0 mol) n-butyl chloride are then metered in under reflux in the course of 2 h, further water being cycled out. After metering, the reaction mixture is stirred for a further 2 h, cooled to 80° C., hydrolysed with 800 g water and adjusted to pH 4 with 50% (m/m) sulphuric acid. The phases are separated at 70° C. After distillation, 794 g product with a purity of 94% is obtained.
Reaction SMILES: [CH2:1]([C:8]([OH:17])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(O[N:26]1[N:34]=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.ONC(=O)CCC(N)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:8]([OH:17])([C:9]([NH:26][NH2:34])=[O:10])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)(Cc1ccccc1)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC(=O)CCC(=O)NO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)(Cc1ccccc1)C(=O)NN
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 133 %

Procedure:
A mixture of 2-benzyl-3-ethoxy-2-hydroxy-3-oxopropanoic acid (250 mg), HATU (479 mg), diisopropylethyl amine (149 mg) and N-hydroxysuccinamide (145 mg) in 4 mL of DMF was stirred at ambient temperature for 1.5 h. The mixture was diluted with ethyl acetate, washed with water. The organic layer was dried with magnesium sulfate and concentrated to give the desired product ethyl 2-benzyl-3-hydrazinyl-2-hydroxy-3-oxopropanoate (352 mg), which was directly used for the next step. To ethyl 2-benzyl-3-hydrazinyl-2-hydroxy-3-oxopropanoate (352 mg) in DCM (5 mL) was added hydrazine (anhydrous, 101 mg) at ambient temperature. Instantaneously the solution turned cloudy and after 15 min the solvent was removed in vacuo to afford the crude title compound as an amorphous solid. LC/MS 275.2 (M+23).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21]([OH:23])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.[F:43][C:44]1[CH:45]=[C:46]([NH:50][CH2:51][CH2:52][CH2:53][N:54]2[N:58]=[N:57][CH:56]=[N:55]2)[CH:47]=[CH:48][CH:49]=1>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[C:7]([O:11][C:12](=[O:13])[N:14]([CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:21](=[O:23])[N:50]([C:46]2[CH:47]=[CH:48][CH:49]=[C:44]([F:43])[CH:45]=2)[CH2:51][CH2:52][CH2:53][N:54]2[N:58]=[N:57][CH:56]=[N:55]2)[CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)([CH3:9])([CH3:8])[CH3:10]
Reactant: Fc1cccc(NCCCn2ncnn2)c1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCn2ncnn2)c2cccc(F)c2)c1)c1ccncc1
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (0.11 ml) and dry DMF (0.002 ml) were added to a stirred suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.060 g) in dry dichloromethane (1 ml) under nitrogen. After 5 min, DIPEA (0.090 ml) was added followed after a further 40 min by 3-fluorophenyl-(3-tetrazol-2-yl-propyl)-amine (0.066 g) and DMAP (0.002 g). After 3 days the solvent was evaporated and the residue was purified by flash chromatography eluting with dichloromethane:methanol (98:2 v/v) to give the title compound as a green foam (0.079 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28]([NH:30][CH3:31])=[O:29])=[C:11]([Br:27])[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:14](=[O:26])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.Br[CH2:48][CH:49]=[C:50]([CH3:52])[CH3:51]>CN(C=O)C>[CH3:51][C:50]([CH3:52])=[CH:49][CH2:48][N:30]([CH3:31])[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:13]2[C:14](=[O:26])[N:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:16][CH2:17][N:12]2[C:11]=1[Br:27])=[O:29]
Reactant: CC(C)=CCBr
Reactant: CNC(=O)c1c(OCc2ccccc2)c2n(c1Br)CCN(Cc1ccc(F)cc1)C2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)=CCN(C)C(=O)c1c(OCc2ccccc2)c2n(c1Br)CCN(Cc1ccc(F)cc1)C2=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cold (0° C.) solution of 8-(benzyloxy)-6-bromo-2-(4-fluorobenzyl)-N-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo-[1,2-a]pyrazine-7-carboxamide (0.24 g, 0.50 mmol) in anhydrous DMF (10 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 0.55 mmol) was added. The reaction mixture was stirred at 0° C. for 15 minutes and treated with 4-bromo-2-methyl-2-butene (0.15 mL, 1.5 mmol; passed through activated basic alumina). The reaction mixture was stirred at rt for 40 minutes and concentrated under vacuum. The residue was partitioned between methylene chloride and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with ethyl acetate. Collection and concentration of appropriate fractions provided the titled product. ES MS M+1=486,488 (1:1)
Reaction SMILES: Cl.[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[N:15]3[CH:21]=[N:20][CH:19]=[C:16]3[S:17][CH:18]=2)[CH2:11][C@@H:10]([O:22][Si](C(C)(C)C)(C)C)[CH2:9]1)=[O:7])[CH:3]=[CH2:4].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C.O>[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[N:15]3[CH:21]=[N:20][CH:19]=[C:16]3[S:17][CH:18]=2)[CH2:11][C@@H:10]([OH:22])[CH2:9]1)=[O:7])[CH:3]=[CH2:4]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cc1csc2cncn12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1csc2cncn12
Reaction time: 0.5 h

Procedure:
Concentrated hydrochloric acid (0.75 ml) is added dropwise to a solution of 732 mg of (3R,5R)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-(imidazo[5,1-b]thiazol-3-yl)methylpyrrolidine in 15 ml of dry acetonitrile under ice cooling, and the mixture is stirred at that temperature for 30 min. The reaction solution is diluted wit 50 ml of ethyl acetate, water is added thereto, and the mixture is rendered weakly alkaline by addition of a saturated aqueous sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The organic layer is washed once with saturated saline, dried over anhydrous magnesium sulfate, and filtered, and the solvent is removed by evaporation under reduced pressure to give a crude product of (3R,5R)-1-allyloxycarbonyl-3-hydroxy-5-(imidazo[5,1-b]thiazol-3-yl)methylpyrrolidine. Triethylamine (0.41 ml) and 0.23 ml of methanesulfonyl chloride are successively added to a solution of this compound in 3 ml of dichloromethane under an argon stream under ice cooling, and the mixture is stirred at that temperature for 2 hr. Water is added to the reaction solution, and the mixture is extracted three times with dichloromethane. The organic layer is washed twice with saturated saline, dried over anhydrous magnesium sulfate, and filtered, and the solvent is removed by evaporation under reduced pressure to give a crude product which is then purified by column chromatography on silica gel (ethyl acetate) to give 428.2 mg of (3R,5R)-1-allyloxycarbonyl-5-(imidazo[5,1-b]thiazol-3-yl)methyl-3-methanesulfonyloxypyrrolidine as a colorless oil.
Reaction SMILES: [CH:1]([O:14][C:15]([CH:17]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:18]([NH:20][CH:21]1[C:40](=[O:41])[N:23]2[C:24]([C:29]([O:31][CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:30])=[C:25]([CH3:28])[C:26](=[O:27])[C@H:22]12)=[O:19])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C(C1C=CC=CC=1)C(NC1C(=O)N2C(C(OCOC(=O)C(C)(C)C)=O)C(C)C(=O)[C@H]12)=O)=O)C1C=CC=CC=1.CC1C(C([O-])=O)N2C(=O)C(NC(=O)C(C(OCC3C=CC4C(=CC=CC=4)C=3)=O)C3C=CC=CC=3)[C@H]2C1=O>>[CH:1]([O:14][C:15]([CH:17]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:18]([NH:20][CH:21]1[C:40](=[O:41])[N:23]2[CH:24]([C:29]([O:31][CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:38])[CH3:36])=[O:30])[CH:25]([CH3:28])[C:26](=[O:27])[C@H:22]12)=[O:19])=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(C(=O)OC(c3ccccc3)c3ccccc3)c3ccccc3)[C@H]2C1=O
Agent: CC1C(=O)[C@@H]2C(NC(=O)C(C(=O)OCc3ccc4ccccc4c3)c3ccccc3)C(=O)N2C1C(=O)[O-]
Agent: CC1C(=O)[C@@H]2C(NC(=O)C(C(=O)OCc3ccccc3)c3ccccc3)C(=O)N2C1C(=O)OCOC(=O)C(C)(C)C
Product: CC1C(=O)[C@@H]2C(NC(=O)C(C(=O)OC(c3ccccc3)c3ccccc3)c3ccccc3)C(=O)N2C1C(=O)OCOC(=O)C(C)(C)C

Procedure:
By the same method the other carbapen-2-em esters of Example 52 are reduced to the corresponding pivaloyloxymethyl 6-(2-benzyloxycarbonyl-2-phenylacetamido)-2-methyl-1-oxocarbapenam-3-carboxylate and 2-methyl-6-[2-(2-napthylmethoxycarbonyl)-2-phenylacetamido]-1-oxocarbapenam-3-carboxylate.